We have measured regional cerebral blood flow (rCBF) with oxygen-15 water and positron emission tomography (PET) in patients with schizophrenia and other neuropsychiatric disorders during performance of a battery of neuropsychological tasks putatively involving working memory and abstract reasoning as well as during performance of matched sensorimotor control tests . In monozygotic twins discordant for schizophrenia, an area of the left inferior frontal gyrus corresponding to Brodmann's Areas 9 and 46 of the dorsolateral prefrontal cortex was lower in affected compared with unaffected twins during a frontal lobe-specific task which consistently activates this area in normal subjects. The left and superior temporal gyrus, discriminated between affected and unaffected co-twins in each and every pair and was more active in each of the ill twins. We have recently further localized this hyperfunctionality as being confined to the anterior (pes) portion of the hippocampal formation as opposed to more posterior hippocampal areas. The functional pattern in the amygdala, if anything, tends to be opposite, i.e. activity tends to be lower in schizophrenia. Subjects with schizophrenia have diminished neurophysiological response in prefrontal cortex while performing two tasks with a strong working memory component, the Wisconsin Card Sorting Test (WCS) and Delayed Response Alternation. This is true even when normal control subjects and those with schizophrenia are matched for cognitive ability on the tasks. In addition to schizophrenia, we are examining other patient groups with relevance to understanding the pathophysiology of the prefrontal cortex, such as closed head injury. In an otherwise normal monozygotic twin who sustained a closed head injury involving the frontal lobe, the cerebral physiological response to solving a frontal lobe task was assessed both relative to his uninjured co-twin and relative to a group of 10 pairs of normal monozygotic twins. Response in the injured twin included recruitment of the hippocampus, an area not typically utilized during performance of this task. In a group of good-outcome patients with serious closed head injury, the brain's physiological response to performing a frontal lobe task involves overrecruitment of some portions of the prefrontal cortex.